Application of micromolecule agonist TEPP-46 in preparation of medicine for preventing and / or treating aortic aneurysm and related cardiovascular diseases
By reprogramming cell metabolism with the small molecule agonist TEPP-46, drugs for the prevention and treatment of aortic aneurysms and related cardiovascular diseases were prepared, which solved the problem of lack of effective drug treatment in the prior art, significantly improved the pathological changes of aortic aneurysms and patient prognosis.
Patent Information
- Application Number
- CN202411911680.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-24
- Publication Date
- 2025-04-04
AI Technical Summary
The prior art lacks effective drug treatment methods to prevent and treat aortic aneurysms and related cardiovascular diseases, and the imaging diagnosis specificity is low, resulting in misdiagnosis and delayed treatment.
Drugs that use the small molecule agonist TEPP-46 as the active ingredient, promote the formation of a highly active tetramer structure of PKM2 and inhibit glycolytic bypass metabolism, thereby reprogramming the metabolic process of cells, and are used to prepare drugs to prevent and treat aortic aneurysms and related cardiovascular diseases.
TEPP-46 significantly improves BAPN-induced aortic dilation, alleviates vascular pathological changes and disruption of elastin arrangement, improves glucose metabolism reprogramming and apoptosis levels of vascular smooth muscle cells, and provides new drug targets to improve patient prognosis.
Smart Images
Figure CN119745887A_ABST
Abstract
Description
Technical Field
[0001] The present invention belongs to the field of biomedicine technology, and specifically relates to the use of a small molecule agonist TEPP-46 in the preparation of drugs for preventing and / or treating aortic aneurysms and related cardiovascular diseases. Background Art
[0002] Aortic aneurysm / dissection is a common degenerative cardiovascular disease, with pathological characteristics of chronic aortic wall inflammation, degradation of extracellular matrix proteins, and dysfunction of vascular smooth muscle cells. The early symptoms of patients are hidden, and aortic rupture may occur in the middle and late stages, leading to hemorrhagic death. The disease has an acute onset, rapid progression, and a high mortality rate. It requires timely surgical treatment. Misdiagnosis or delayed treatment can cause permanent damage or death. However, imaging diagnosis is difficult to popularize, existing biomarkers have low specificity, and there is no effective drug treatment. Therefore, further clarifying the pathogenesis of aortic aneurysm / dissection and using this as a target to find drugs and treatments with potential clinical application value will significantly enhance the clinical benefits of aortic aneurysm / dissection and improve patient prognosis, which is of great clinical significance.
[0003] The small molecule drug TEPP-46 is a specific small molecule agonist of pyruvate kinase M2 (PKM2). It can reprogram the metabolic process of cells by promoting the formation of a highly active tetramer structure of PKM2 and inhibiting glycolytic bypass metabolism. PKM2 plays an important role in cell metabolic remodeling, proliferation, and signal transduction. During the formation of aortic aneurysm / dissection, the phenotypic transformation of vascular smooth muscle cells is accompanied by the metabolic reprogramming of glucose, that is, the characteristic change from oxidative phosphorylation to aerobic glycolysis. It is worth noting that the metabolic regulation of TEPP-46 may have potential effects on metabolic-related diseases. However, there are currently no reports on the role of TEPP-46 in the prevention and treatment of aortic aneurysm / dissection. Summary of the invention
[0004] The purpose of the present invention is to provide a small molecule agonist TEPP-46 for use in the preparation of a method for preventing and / or treating aortic aneurysms and related cardiovascular diseases. TEPP-46 can slow down the disease progression of aortic aneurysms and aortic dissecting aneurysms and improve the prognosis of patients, thereby providing a new target for their clinical medical treatment.
[0005] To achieve the above object, the present invention adopts the following technical solution:
[0006] The first aspect of the present invention is the use of the small molecule agonist TEPP-46 in the preparation of a drug for preventing and / or treating aortic aneurysm and related cardiovascular diseases.
[0007] Preferably, the aortic aneurysm and related cardiovascular diseases include aortic aneurysm and aortic dissecting aneurysm.
[0008] Preferably, the drug is a targeted drug.
[0009] Preferably, the drug uses the small molecule agonist TEPP-46 as an active ingredient and uses the PKM2 protein as a target.
[0010] Preferably, the drug further comprises a pharmaceutically acceptable carrier selected from one or a combination of two or more of a buffer, an encapsulating agent, a filler, an adhesive, a transdermal absorbent, a wetting agent, a disintegrant, an absorption enhancer, a surfactant, a colorant, a flavoring agent and an adsorption carrier.
[0011] Preferably, the drug is prepared as a pharmaceutically acceptable drug preparation, and the dosage form is selected from one or a combination of two or more of tablets, capsules, pills, granules, suspensions, oral liquids, coatings, papules, sprays, powder injections and water injections.
[0012] Compared with the prior art, the present invention has the following beneficial effects:
[0013] The present invention discloses for the first time that the small molecule agonist TEPP-46 has a protective effect on aortic aneurysm / dissection vascular damage and can be used to prepare drugs for preventing / treating aortic aneurysm / dissection. Animal experiments show that TEPP-46 can significantly improve BAPN-induced aortic dilatation, reduce BAPN-induced vascular pathological changes and elastin arrangement damage, and improve the reprogramming of glucose metabolism and apoptosis levels of vascular smooth muscle cells caused by aortic aneurysm / dissection. BRIEF DESCRIPTION OF THE DRAWINGS
[0014] Figure 1 The figures are related to the gross images and survival rate results of TEPP-46 improving BAPN-induced aortic aneurysm / dissection vascular injury in mice in the examples.
[0015] Figure 2 The vascular ultrasound detection and maximum aortic diameter statistical results of TEPP-46 alleviating BAPN-induced aortic dilatation in the examples are shown.
[0016] Figure 3 The results of HE staining and EVG staining show that TEPP-46 alleviates BAPN-induced aortic aneurysm / dissection in mice during the formation process and destruction of elastin arrangement.
[0017] Figure 4 In this example, TEPP-46 improves the glucose metabolism reprogramming of mouse vascular smooth muscle cells during BAPN-induced aortic aneurysm / dissection.
[0018] Figure 5The results of Western blot and TUNEL staining in the example show that TEPP-46 alleviates the apoptosis of mouse vascular smooth muscle cells during the formation of aortic aneurysm / dissection induced by BAPN. DETAILED DESCRIPTION
[0019] In order to more fully understand and demonstrate the technical solutions, purposes and advantages of the present invention, the technical effects produced by the present invention are further described in detail and completely in conjunction with the accompanying drawings and specific embodiments. Obviously, the described embodiments are only part of the embodiments of the present invention, not all. It should be pointed out that for ordinary technicians in this field, other embodiments obtained without departing from the concept of the present invention all belong to the protection scope of the present invention.
[0020] The following examples provide the use of TEPP-46 in the prevention and treatment of aortic aneurysm / dissection.
[0021] Example 1
[0022] 1. Experimental methods
[0023] 1.1 Establishment of mouse aortic aneurysm / dissection model. The specific steps are as follows:
[0024] Forty male 4-week-old C57BL / 6J mice were randomly divided into two groups: control group and BAPN experimental group, with 20 mice in each group. The experimental group was given BAPN (1g / kg / day) in water to prepare the mouse AAD model, while the control group drank normal drinking water. After vascular ultrasound evaluation on the 28th day, the mice were anesthetized with CO2 and killed. The aorta was isolated to observe and judge the formation and severity of AAD in the experimental group.
[0025] TEPP-46 was purchased from Selleck (Cat. No. S7302). After BAPN feeding for 2 weeks, mice were given TEPP-46 (10 mg / kg) daily by oral gavage.
[0026] 1.2 Vascular ultrasound assessment of aortic dilatation in mice
[0027] Mice were anesthetized with 2% isoflurane and fixed on an ultrasound table in a supine position with their head facing forward. An electrocardiogram was connected to maintain a heart rate of 400-500 beats / min. Transthoracic micro-ultrasound imaging (MUI) was performed on mice using a Vevo 2100 Doppler ultrasound system to evaluate the morphological characteristics of aortic aneurysms / dissections in vivo. MUI images were acquired in B-mode according to the manufacturer's instructions, and the aortic diameter was measured three times by a blinded experimenter to confirm the maximum aortic dilation.
[0028] 1.3 TUNEL staining assay
[0029] The TUNEL apoptosis detection kit of Shanghai Bio-Tech was used to evaluate the apoptosis level of vascular smooth muscle cells in aorta tissue. The specific steps were as follows: treat tissue sections with fixative and fix at room temperature for 30 minutes; aspirate the fixative and add perforation solution and incubate at room temperature for 15 minutes; aspirate the perforation solution and add 5% BSA to block at room temperature for 1 hour; add 50 μL TUNEL detection solution and incubate at 37°C in the dark for 60 minutes; aspirate the blocking solution and add the prepared primary antibody to the tissue, making sure that the primary antibody covers the tissue sufficiently for each sample, place the slide in a humidified box and keep it at 4°C overnight; aspirate the primary antibody, add the secondary antibody after washing, and incubate at room temperature in the dark for 1 hour; aspirate the secondary antibody and wash 3 times; seal the slide with DAPI anti-quenching sealing agent, making sure that the coverslip is tight to the tissue patch and there are no bubbles, and take pictures with a confocal microscope.
[0030] After BAPN was continuously fed with water for 28 days, vascular ultrasound was used to detect the maximum aortic diameter of mice, HE staining and EVG staining were used to detect vascular pathological changes and elastin arrangement, seahorse was used to detect glycoPER level of vascular smooth muscle glycolysis, Western blot and TUNEL staining were used to detect apoptosis of vascular smooth muscle cells in mice in different treatment groups.
[0031] 2. Experimental results
[0032] (1) The gross image of mouse aorta and the survival rate results are as follows Figure 1 As shown, TEPP-46 can improve the formation of aortic aneurysm / dissection induced by BAPN.
[0033] (2) The results of the mouse vascular ultrasound examination are as follows Figure 2 As shown, TEPP-46 was shown to attenuate BAPN-induced aortic dilatation.
[0034] (3) HE staining and EVG staining results are as follows Figure 3 As shown, TEPP-46 significantly alleviated BAPN-induced aortic aneurysm / dissection in mice vascular pathological changes and elastin arrangement disorder.
[0035] (4) Seahorse detection shows Figure 4 As shown, TEPP-46 was shown to ameliorate the reprogramming of glucose metabolism in mouse vascular smooth muscle cells during BAPN-induced aortic aneurysm / dissection.
[0036] (5) WB and TUNEL staining results are as follows Figure 5 As shown, TEPP-46 significantly alleviated BAPN-induced aortic aneurysm / dissection in mice with vascular smooth muscle cell apoptosis.
[0037] In summary, the present invention reveals for the first time that TEPP-46 can improve aortic aneurysm / dissecting vascular damage, providing a new drug target for the diagnosis and treatment of aortic aneurysm / aortic dissecting aneurysm, and has important clinical application value.
[0038] The above are only preferred embodiments of the present invention and are not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.
Claims
1. Use of the small molecule agonist TEPP-46 in the preparation of drugs for preventing and / or treating aortic aneurysms and related cardiovascular diseases.
2. The use according to claim 1, characterized in that: The aortic aneurysm and related cardiovascular diseases include aortic aneurysm and aortic dissecting aneurysm.
3. The use according to claim 1, characterized in that: The drug is a targeted drug.
4. The use according to claim 1, characterized in that: The drug uses the small molecule agonist TEPP-46 as an active ingredient and targets the PKM2 protein.
5. The use according to claim 1, characterized in that: The drug also includes a pharmaceutically acceptable carrier, selected from one or a combination of two or more of a buffer, an encapsulating agent, a filler, a binder, a transdermal absorbent, a wetting agent, a disintegrant, an absorption promoter, a surfactant, a colorant, a flavoring agent and an adsorption carrier.
6. The use according to claim 1, characterized in that: The drug is prepared as a pharmaceutically acceptable drug preparation, and the dosage form is selected from one or a combination of two or more of tablets, capsules, pills, granules, suspensions, oral liquids, coatings, papules, sprays, powder injections and water injections.